Development of E1A Gene Therapy in Ovarian Cancer

卵巢癌E1A基因疗法的进展

• 批准号: 7729373
• 负责人: MIEN-CHIE HUNG
• 金额: $ 14.74万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-04 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7729373
• 关键词: Animal Model; Appendix; Biopsy; Breast; Cancer Center; Cancer Model; Cancer Patient; Chemosensitization; Clinical; Clinical Data; Clinical Trials; Combined Modality Therapy; Complex; Control Groups; Cytotoxic agent; Data; Development; Dose; Drug usage; ERBB2 gene; Elements; Eligibility Determination; Ensure; Fc Receptor; Folate; Funding; Future; Gene Expression; Goals; Iron; Ligands; Liposomes; Malignant neoplasm of ovary; Maximum Tolerated Dose; Mediating; Monitor; Numbers; Paclitaxel; Patients; Peptides; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Progress Reports; Progression-Free Survivals; Protein Overexpression; Randomized; Rate; Recurrence; Refractory; Reporting; Reproduction spores; System; TNFSF10 gene; Testing; Therapeutic; Toxic effect; Tumor Suppressor Proteins; Upper arm; Woman; Xenograft procedure; base; cancer cell; chemotherapy; design; experience; expression vector; gene delivery system; gene therapy; improved; insight; intraperitoneal; novel; pre-clinical; preclinical study; promoter; response

During the previous funding period, we defined multiple antitumor activities associated with E1A gene expression and established an appropriate animal model to evaluate the anti-ovarian cancer activity of an E1Aliposome complex. A phase I study using ElA-liposome complex targeting of breast and ovarian cancers was completed and reported during the previous funding period (Appendix 1-J. Clin. Oncol. 19:3422-3433, 2001). Based on this experience, we initiated a phase II trial of intraperitoneal single-agent E1A gene therapy in patients with recurrent ovarian cancer in 2001. Because of the small number of patients who met the eligibility requirements, we terminated the phase II trial and initiated a new phase l/ll trial that combines chemotherapy with E1A gene therapy and that has more appropriate eligibility requirements. This phase l/ll trial has been opened and has begun to accrue patients. In the competitive renewal, we will continue both preclinical studies and clinical trials to ensure the development of an effective therapeutic approach for ovarian cancer that utilizes gene therapy. To achieve this goal, we propose the following three Specific Aims: Specific Aim 1: To complete the phase l/ll trial of E1A gene therapy combined with chemotherapy. Using a novel trial design, we will perform a randomized phase l/ll trial in which one arm receives weekly i.v. paclitaxel (to establish a concurrent control group for a heterogeneous group of patients) and the other arm receives weekly i.v. paclitaxel with i.p. liposomal E1A gene therapy at different does levels. This study will define the toxicity, maximum tolerated dose (MTD), clinical response rate, and progression-free survival of weekly paclitaxel plus E1A-\\p\d complex treatment. Biopsies will be obtained to monitor therapy at the cellular level. Specific Aim 2: To develop an ovarian cancer-specific gene delivery system and expression vector. Two approaches will be used to improve systemic i.v. targeting of E1A gene therapy to treat ovarian cancer xenografts: 1) development of ovarian cancer-specific promoter elements and 2) conjugation of liposomes with targeting peptides, folate ligand, and anti¿folate receptor antibodies. Specific Aim 3: To develop an effective combination of E1A gene therapy with other agents in a preclinical ovarian cancer model. Using ovarian cancer xenografts, we will test the efficacy and toxicity of E1A gene therapy in combination with cytotoxic drugs used to treat ovarian cancer patients as well as novel biologic agents (TNFa and TRAIL). Preliminary data suggest that these agents may exert synergistic antitumor activity at subtoxic doses. The clinical data from Aim 1 and preclinical insights from Aims 2 and 3 can be combined in the future to design novel and potentially even more effective therapeutic strategies.

在上一个资金期间，我们定义了与E1A基因相关的多种抗肿瘤活性 表达并建立了一个适当的动物模型，以评估E1aliposom的抗卵巢癌活性 复杂的。使用乳腺癌和卵巢癌的ELA脂质体复合物靶向的I期研究是 在上一个资金期间完成并报告（附录1-J。Clin。Oncol。19：3422-3433，2001）。 根据这一经验，我们开始了腹膜内单药E1A基因治疗II期试验 2001年复发性卵巢癌患者。由于符合资格的患者数量少 要求，我们终止了II期试验，并启动了一项新的L/LL试验，该试验结合了化学疗法 使用E1A基因疗法，并且具有更合适的资格要求。该阶段L/LL试验已经 开放并已开始累积患者。在竞争性更新中，我们将继续两项临床前研究 和临床试验，以确保开发有效的卵巢癌治疗方法 利用基因疗法。为了实现这一目标，我们提出以下三个特定目标：特定目的1： 完成E1A基因疗法的L/LL试验结合化疗。使用新颖的审判 设计，我们将进行一项随机L/LL试验，其中一个ARM每周接收i.v.紫杉醇（TO 为异构患者组建立一个并发的对照组），另一只手臂每周接收 I.V.紫杉醇带有i.p.脂质体E1a基因治疗在不同的水平上。这项研究将定义毒性， 最大耐受剂量（MTD），临床反应率和每周紫杉醇的无进展生存 E1A - \\ P \ D复杂处理。将获得活检以监测细胞水平的治疗。具体目标 2：开发卵巢癌特异性基因递送系统和表达载体。两种方法 将用于改善系统性i.v.靶向E1A基因治疗以治疗卵巢癌的特征：1） 开发卵巢癌特异性启动子元素和2）脂质体与靶向的结合 肽，叶酸配体和抗叶酸受体抗体。特定目标3：开发有效 在临床前卵巢癌模型中，E1A基因治疗与其他药物的组合。使用 卵巢癌特征，我们将测试E1A基因治疗的效率和毒性 细胞毒性药物用于治疗卵巢癌患者以及新型生物学剂（TNFA和TRAIL）。 初步数据表明，这些药物可能会以潜意性的剂量发挥协同抗肿瘤活性。这 AIM 1和AIM 2和3的临床前见解的临床数据可以在未来组合使用以设计 新颖，可能更有效的治疗策略。